UBC Cryo-EM Study Maps Three-Molecule Statin Binding to RyR1 Explaining Muscle Calcium Leak

The 2026 Nature Communications paper from lead author Steven Molinarolo and senior author Filip Van Petegem details how the first statin molecule primes the closed channel for opening while the next two stabilize the open state. This structural mechanism was resolved at near-atomic resolution in the UBC high-resolution cryo-EM facility using muscle-derived RyR1 complexes. The finding directly addresses why muscle symptoms affect up to 10-15% of the more than 200 million statin users worldwide even though severe rhabdomyolysis remains rare.

Existing explanations for statin myopathy have focused on HMG-CoA reductase inhibition, CoQ10 depletion, or mitochondrial stress, yet none fully accounted for the rapid onset of pain in some patients. The new RyR1 data supplies a channel-level route that can operate alongside metabolic effects and may explain why symptoms vary sharply between individuals with different RyR1 variants. It also suggests why switching statins or dose reduction sometimes fails to resolve pain.

Drug developers can now target the specific binding pocket to retain HMG-CoA reductase affinity while eliminating RyR1 interaction. Parallel work on related ryanodine receptor isoforms could extend the approach to other calcium-channel drugs. Clinical translation will require both cell and animal models that quantify calcium leak before human trials of modified molecules begin.